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TPC2-A1-P Sale

目录号 : GC63234

TPC2-A1-P 是一种强大的膜渗透性的双孔通道 2 (TPC2) 激动剂 (EC50=10.5 μM),它通过模仿 PI(3,5)P2 的生理作用发挥作用。与 TPC2-A1-N 相比,TPC2-A1-P 具有更高的诱导 Na+ 活化的能力,可用于检测完整细胞中 TPC2 通道的不同功能。

TPC2-A1-P Chemical Structure

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥2,736.00
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5 mg
¥2,700.00
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10 mg
¥4,500.00
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25 mg
¥8,550.00
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50 mg
¥13,950.00
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100 mg
¥21,150.00
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Sample solution is provided at 25 µL, 10mM.

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产品描述

TPC2-A1-P is a powerful and membrane permeable agonist of two pore channel 2 (TPC2) with an EC50 of 10.5 μM. TPC2-A1-P plays its role by mimicking the physiological actions of PI(3,5)P2. TPC2-A1-P also shows higher potency to induce Na2+ mobilisation from TPC2 than TPC-A1-N . TPC2-A1-P can be used to probe different functions of TPC2 channels in intact cells[1][2][3].

Two-pore channels (TPC1-3) are ancient members of the voltage-gated ion channel superfamily. TPCs are expressed throughout the endo-lysosomal system and regulates the trafficking of various cargoes[1].TPC2 can mediate different physiological and possibly pathophysiological effects depending on how it is activated. The ion selectivity of TPC2 is not fixed but rather agonist-dependent. TPC2 is a unique example of an ion channel that conducts different ions in response to different activating ligands[1].TPC2-A1-P (10 μM) reproducibly evokes Ca2+ signals, and TPC2-A1-P response reachs its plateau slower than TPC2-A1-N . The EC50 in full concentration-effect relationships for the plateau response is 10.5 μM for TPC2-A1-P in a cell line stably expressing TPC2L11A/L12A.TPC2-A1-P (10-30 μM) induces Ca2+ signals in Hela cells expressing TPC2 in the presence but not absence of extracellular Ca2+. However, the responses are smaller and delayed compared to TPC2-A1-N , consistent with the results obtained in cells stably expressing TPC2L11A/L12A. TPC2-A1-P fails to induce Ca2+ signals in cells expressing ’pore-dead’ TPC2L11A/L12A/L265P and also fails to evoke Ca2+ signals in cells expressing human TRPML1 re-routed to the plasma membrane (TRPML1δNC)[1].In endo-lysosomal patch-clamp experiments, TPC2-A1-P (10 μM) evokes currents in endo-lysosomes isolated from cells expressing TPC2 and TPC2M484L, the currents evoked by TPC2-A1-P are significantly larger than those evoked by TPC2-A1-N in both wild-type and gain-of-function variant,and exhibits an EC50 value of 0.6 μM for TPC2-A1-P[1].

[1]. Susanne Gerndt, et al. Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function. Elife. 2020 Mar 16;9:e54712. [2]. Gerndt S, et al. Discovery of lipophilic two-pore channel agonists. FEBS J. 2020;287(24):5284-5293. [3]. Xuhui Jin, et al. Targeting Two-Pore Channels: Current Progress and Future Challenges. Trends Pharmacol Sci. 2020 Aug;41(8):582-594.

Chemical Properties

Cas No. SDF
分子式 C20H21BrF3NO3 分子量 460.28
溶解度 DMSO : 50 mg/mL (108.63 mM; Need ultrasonic) 储存条件 Store at -20°C
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1 mM 2.1726 mL 10.863 mL 21.7259 mL
5 mM 0.4345 mL 2.1726 mL 4.3452 mL
10 mM 0.2173 mL 1.0863 mL 2.1726 mL
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Research Update

Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue!

Cells 2022 Sep 8;11(18):2807.PMID:36139381DOI:10.3390/cells11182807.

Lysosomal storage diseases (LSDs) resulting from inherited gene mutations constitute a family of disorders that disturb lysosomal degradative function leading to abnormal storage of macromolecular substrates. In most LSDs, central nervous system (CNS) involvement is common and leads to the progressive appearance of neurodegeneration and early death. A growing amount of evidence suggests that ion channels in the endolysosomal system play a crucial role in the pathology of neurodegenerative LSDs. One of the main basic mechanisms through which the endolysosomal ion channels regulate the function of the endolysosomal system is Ca2+ release, which is thought to be essential for intracellular compartment fusion, fission, trafficking and lysosomal exocytosis. The intracellular TRPML (transient receptor potential mucolipin) and TPC (two-pore channel) ion channel families constitute the main essential Ca2+-permeable channels expressed on endolysosomal membranes, and they are considered potential drug targets for the prevention and treatment of LSDs. Although TRPML1 activation has shown rescue effects on LSD phenotypes, its activity is pH dependent, and it is blocked by sphingomyelin accumulation, which is characteristic of some LSDs. In contrast, TPC2 activation is pH-independent and not blocked by sphingomyelin, potentially representing an advantage over TRPML1. Here, we discuss the rescue of cellular phenotypes associated with LSDs such as cholesterol and lactosylceramide (LacCer) accumulation or ultrastructural changes seen by electron microscopy, mediated by the small molecule agonist of TPC2, TPC2-A1-P, which promotes lysosomal exocytosis and autophagy. In summary, new data suggest that TPC2 is a promising target for the treatment of different types of LSDs such as MLIV, NPC1, and Batten disease, both in vitro and in vivo.

The name tells the story: Two-pore channels

Cell Calcium 2020 Jul;89:102215.PMID:32442744DOI:10.1016/j.ceca.2020.102215.

TPC2-A1-N and TPC2-A1-P, two novel small molecules, differentially activate two-pore channel 2 (TPC2) and mimic the activation of TPC2 with NAADP and PIP2, resulting in distinct ion channel selectivities. These two different modes of TPC2 activity have physiological, and possibly pathophysiological, implications as they can modulate vesicle trafficking and lysosomal exocytosis.